The specific aims remain essentially the same for this long-running project; i.e., to elucidate how adiposity signals interact with the brain to influence food intake and body weight. The adiposity signals now include leptin as well as insulin. Specific Aim 1 will determine the interactions of insulin with the hypothalamic propiomelanocoritin (POMC) and neuropeptide Y (NPY) systems. The hypothesis driving the experiments is that insulin will potentiate the POMC system and inhibit the NPY system. Specific Aim 2 will determine the interactions of insulin and leptin within the brain. The hypothesis is that the two peptides will synergistically elicit a net catabolic action. Specific Aim 3 will assess the hypothesis that a major gender difference exists in the central control of energy homeostasis, with insulin controlling the male system and leptin controlling the female system. Finally, Specific Aim 4 will determine the effect of eliminating insulin signaling in the brain by creating mice with brain-specific insulin receptor deletions. All of the experiments are directly relevant to emerging therapeutic approaches to the treatment of obesity.